Adipose Tissue Hypoxia and Inflammation in Obesity Abstract: Recent studies from several labs including ours consistently support that adipose tissue hypoxia (ATH) may be responsible for the initiation of chronic inflammation and adipose tissue dysfunction in obese subjects. The observations have been reported in both human and mice. The biological significance of ATH has been highlighted in several review articles about inflammation and adipose tissue function in obesity. However, the uptream and downstream events of ATH remains unknown in vivo. Based on our data, we hypothesize that the chronic inflammation represents a major event of hypoxia response in the adipose tissue in obesity. To test this hypothesis, we would propose three specific aims. AIM I. To test that adipose tissue hypoxia is a result of blood flow reduction. Blood flow and oxygen tension will be examined in adipose tissue to test the relationship in vivo. Diet-induced obese mice and ob/ob mice will be used. AIM II. To determine that the blood flow reduction is a consequence of microcirculation failure in the adipose tissue. The microcirculation will be investigated by analyzing vascular structure and function. The study will focus on angiogenesis, and vasodilation. Angiogenic factors and vessel tone regulators will be analyzed during adipose tissue growth. AIM III. To test that inflammation mediates the hypoxia signal in the regulation of adipose tissue vasculature. A role of macrophage in angiogenesis will be investigated in adipocyte-specific NF-kB p65 knockout mice. We expect that in the absence of NF-kB p65, macrophage function will be decreased in adipose tissue and angiogenesis will be defective. We expect that this study will provide a novel mechanism for chronic inflammation and adipose tissue dysfunction in obesity. Adipose tissue hypoxia has potential to be a new biomarker for early diagnosis of insulin resistance. PUBLIC HEALTH RELEVANCE: Inflammation in obesity contributes to many chronic diseases in obese patients. Understanding of the mechanism of inflammation will help us to develop strategies in prevention and treatment of the chronic diseases, such as type 2 diabetes, hypertension, heart attack, atherosclerosis, hyperglycemia, renal failure and blindness. However, the current knowledge is not sufficient to provide a clear molecular target in preventive or therapeutic intervention of these diseases. In this study, we plan to identify the earlier biomarkers for diagnosis of the inflammation and insulin resistance in obese condition.